International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family

Abstract

Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca(2+) and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.

Fig. 1.

TRPC (canonical) family. A, molecular domains of TRPC channels and their current-voltage relationships. The TRP box is a conserved region in TRPC, TRPV, and TRPM families; its function is unclear, but it may bind PIP₂. CIRB refers to a calmodulin/IP₃R-binding (CIRB) domain. The EF hand is a helix-loop-helix structural domain found in a large family of calcium-binding proteins. PDZ (postsynaptic density 95/disc-large/zona occludens) is a common protein interaction motif that holds together signaling complexes. In this and the following figures, steady state current-voltage curves are shown. B, results of genetic deletion experiments. The TrpC7(−/−) phenotype has not been reported. TrpC2 is a pseudogene in humans.

Fig. 2.

TRPV (vanilloid) family. A, molecular domains of TRPV channels and their current-voltage relationships. The ankyrin repeat is an ∼33-residue motif consisting of two α helices separated by loops. This region in TRPV1 binds ATP. B, results of genetic deletion experiments.

Fig. 3.

TRPM (melastatin) family. A, molecular domains of TRPM channels and their current-voltage relationships. NUDIX is a phosphohydrolase family homologous region in TRPM2 that binds ADP ribose. TRM6 and TRPM7 possess a C-terminal serine/threonine kinase that is similar in structure to protein kinase A. B, results of genetic deletion experiments.

Fig. 4.

TRPA1 (ankyrin repeat), TRPML (mucolipin) and TRPP [polycystic kidney disease 2 (PKD2), also called polycystin 2 (PC2)] channels. A, “distal” TRP molecular domains and their current-voltage relationships. The ER retention signal is a small domain that presumably maintains the channel in the endoplasmic reticulum. Note that the current-voltage relationship for TRPA1 shows decay at positive potentials in most whole-cell recordings and is linear with electrophilic agonist. B, major phenotypes in “distal” TRP channel knockout mice. Note: the PKD1 refers to the 11-TM domain-containing protein of the polycystin 1 family. TRPP (PKD2, polycystin 2, PC2) refers to the 6-TM family of proteins.